Genetic variation in cytokine promoter regions is postulated to influence
susceptibility to infection, but the molecular mechanisms by which such polymorphisms
might affect gene regulation are unknown. Through systematic DNA footprinting
of the TNF (encoding tumour necrosis factor, TNF) promoter region,
we have identified a single nucleotide polymorphism (SNP) that causes the
helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex
protein-DNA interactions and alters gene expression in human monocytes. The
OCT-1-binding genotype, found in approximately 5% of Africans, is associated
with fourfold increased susceptibility to cerebral malaria in large case-control
studies of West African and East African populations, after correction for
other known TNF polymorphisms and linked HLA alleles.
